The cessation of ethanol consumption is difficult and often unsuccessful, even for highly motivated patients. Abrupt termination of ethanol-exposure renders the brain vulnerable to neurological sequelae, including sensorimotor impairment, tremor, and convulsions, which discourage the patient's efforts to stop consuming alcohol. The only available treatment for the ethanol withdrawal (EW) distress is benzodiazepines but the side effects (e.g. dependency and respiratory depression) limit clinical use of this treatment. In a rat model of ethanol intoxication and withdrawal, we recently demonstrated profound brain protection by daily cycles of 5-10 minutes, intermittent, normobaric, moderate (FIO2 9.5-10%) hypoxia (IH). In our pilot studies, when IH treatment was applied during the last 20 days of an ethanol diet, it attenuated the overt behavioral signs of EW (e.g. tremor and rigidity);EW-induced mitochondrial membrane swelling;and cytotoxicity. In particular, EW provoked a more than 6-fold increase in the proapoptotic kinase P38;IH conditioning almost completely suppressed this increase in ethanol withdrawn rats. Interestingly, all of these IH protections were more effective during EW than during ethanol-exposure, implicating that IH counteracts factors mediating EW. These remarkable results suggest that adaptation to intermittent normobaric hypoxia could provide a safe and effective treatment complementary to conventional benzodiazepines. Using a repeated withdrawal paradigm, we intend to define behavioral phenotypes of IH protection with various treatment windows of IH and cellular mechanisms involving P38 by which IH protects against repeated EW. We hypothesize that IH conditioning applied during the initial cycle of EW exerts persistent protection against behavioral and brain injury throughout repeated EW. Rats will receive two cycles of an ethanol diet (7.5%) for 5 weeks and abrupt withdrawal for 20 days. IH conditioning will be applied to the initial cycle of the EW or the ethanol-exposure phase. We will determine 1) whether IH treatment during the initial cycle of EW protects against overt behavioral signs of EW and cerebellum-/hippocampus-related behavioral deficit and whether the protection persists throughout the repeated EW;2) whether IH-induced suppression of P38 activity mediates protection against apoptotic (programmed cell death) brain injury and whether the protection persists throughout the repeated EW in a manner that correlates with behavioral protection. Some animals will receive the P38 inhibitor SB203580 to define the role of P38-inhibition in the IH protection. Defining the IH-induced behavioral and brain protection against EW insults and identifying an optimal treatment window may establish foundation data necessary for the development of an alternative management of EW. PUBLIC HEALTH RELEVANCE: Alcoholics failed to achieve complete abstinence due to distress associated with sudden termination of drinking. We observed that cycles of intermittent brief (5 to 8 min) and moderate hypoxia (9 to 10% oxygen) conditioning reduced signs of ethanol withdrawal (e.g. tremor and rigidity) and oxidative stress in rats. Information on intermittent hypoxia-evoked brain protection from ethanol withdrawal distress resulting will establish an empirical foundation to support eventual clinical application for a better management of alcoholism in which ethanol withdrawal plays a key role.